Varicose veins are swollen and knotted veins that are both unsightly and uncomfortable. Up to 20% of the adult population have varicose veins and experience discomfort as a result. They can cause swelling of the legs and feet and the skin to itch. Factors such as prolonged standing or sitting, obesity and pregnancy play a large part in the development of varicosity. Varicose veins can occur in almost any part of the body, however they most often occur in the calf or on the inside of the leg between the groin and the ankle.
Hemorrhoids are a varicose dilation of the veins around the anus. Hemorrhoids are similar to varicose veins in the legs, in that the supporting walls of the veins weaken. According to the National Institutes of Health, about half of the United States population over age 50 suffer from hemorrhoids. While most hemorrhoids are not serious, they can have a major effect on one's quality of life. Prevention and treatment of hemorrhoids can include dietary changes, stool softeners, sitz baths and application of conventional topical anti-inflammatory ointments, such as Hemorid, Hemcure, Hemorr-X, Delicare, Preparation H and Ultroid. In more extreme cases, destroying the hemorrhoid by freezing or heating, ligation of the hemorrhoid or even laser surgery may be warranted. There are also a variety of traditional remedies available in India, China and other countries.
Alkaloids are basic nitrogenous organic compounds of plant origin. Isoquinoline alkaloids are a class of alkaloids derived from isoquinoline which has the following structure: ##STR1##
Aporphine alkaloids, are a class of isoquinoline alkaloids, which have the following general structure: ##STR2##
wherein R.sub.1, and R.sub.2 are independently selected from the group consisting of H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl or substituted alkenyl, methylene; R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7 and R.sub.8 are independently selected from the group consisting of H, hydroxy, thiol, methoxy, methyl sulfide, methylenedioxy, alkoxy, alkyl sulfide or pharmaceutically acceptable acid addition salts, selected from the group consisting of chloride, iodide, fluoride, sulfate, phosphate, acetate or carbonate. Apolphine alkaloids have been isolated from the genera of more than twenty plant families, including but not limited to, Araceae, Aristolochiaceae, Berberidaceae, Euphorbiaceae, Helleboraceae, Lauraceae, Magnoliaceae, Menispermaceae, Papaveraceae, Ranunculaceae, Rhamnaceae and Rutaceae. Within these plant families aporphine alkaloids have been isolated from species in numerous genera, including but not limited to, Aconitum, Aristolochia, Berberis, Chelidonium, Clemnatis, Cocculus, Coplis, Dioscoreophyllum, Epimedium, Fumaria, Glaucium, Magnolia, Mahonia, Manodora, Nandina, Pachygone, Phellodendron, Ranunculus, Sinomenium, Thalictrum, Tinospora and Zanthoxylunm. Aporphine alkaloids can be isolated from the whole plant, stems, stem bark, twigs, tubers, flowers, fruits, roots, root barks, young shoots, seeds, rhizomes and aerial parts. To date, more than 500 aporphine alkaloids have been synthesized and/or isolated from more than 90 genera of plants.
Aporphine alkaloids have been reported as having diverse biological activity. Compounds within this class of alkaloids have been patented for the treatment of duodenal ulcers and epileptic seizures (U.S. Pat. Nos. 4,543,256 and 4,543,256), cardiac arrhythmia (U.S. Pat. No. 5,594,033), hypertension (U.S. Pat. No. 4,120,964) and colds and allergies (U.S. Pat. No. 4,461,895). Compounds within this class of alkaloids have also been reported to enhance dopaminergic activity by inactivating a dopamine receptor (U.S. Pat. Nos. 4,353,912 and 4,687,773), improve circulatory performance (U.S. Pat. Nos. 4,761,417 and 5,153,178) and improve wound-healing (U.S. Pat. Nos. 5,156,847 and 5,474,782). Finally, compounds within this class of alkaloids have been reported as an antidote to counteract the effects of cocaine, as appetite suppressants (U.S. Pat. No. 5,258,384), as having analgesic and antitussive effects (U.S. Pat. Nos. 4,358,592, 4,265,912 and 4,315,010) and antipsychotic or sedative effects (U.S. Pat. No.4,687,773). A number of these compounds have been prepared by synthetic processes (see, e.g., U.S. Pat. Nos. 4,309,542 and 4,202,980).
Magnoflorine (see FIG. 1) is a typical aporphine alkaloid, which is widely distributed in a number of plant families, including but not limited to, Aristolochiaceae, Berberidaceae, Helleboraceae, Magnoliaceae, Menispermaceae, Papaveraceae, Ranunculaceae, Rhamnaceae and Rutaceae. Magnoflorine has been shown to decrease arterial blood pressure by activation of the nicotinic receptors in the parasympathetic ganglia and the release of the vasodilator ACh in a dose-dependent manner, without affecting the heart rate and the respiration; induce dose-dependent hypothermia resulting from peripheral vasodilation: induce contractions of isolated rat uterus; and suppress the induction phase, but not the effector phase of the cellular immune response. This compound has also been reported as having antimicrobial activity, significant cytotoxicity, and to inhibit lipoxygenase. To date there have been no reports of the use of this compound for the prevention and treatment of venous insufficiency.
Benzophenanthridine alkaloids, are another class of isoquinoline alkaloids having the following structure: ##STR3##
wherein R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are independently selected from the group consisting of H, hydroxy, alkoxy, methoxy, methylenedioxy, thiol, methyl sulfide and alkyl sulfide; and R.sub.5 is selected from the group consisting of H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl and substituted alkenyl. Benzophenanthridine alkaloids have been isolated from the genera of numerous plant families, including but not limited to, Rutaceae, Fumariaceae, Papaveraceae, Caprifoliaccae, Mrliaceae. Within these plant families these alkaloids can be isolated from numerous genera including, but not limited to, Zanthoxylum, Xanthoxylium, Toddalia, Chelidonium, Papaver, Hypecoum, Hylonlecon, Prantl, Argemone, Eschscholtxia, Sanguinaria, Corydalis, Dicentra, Fumaria, Fagara, Symphoricarpos, Bocconia, Xylocarpus, and Mocleaya. Benzophenanthridine alkaloids have also been reported as having diverse biological activity. Chelerythrine (see FIG. 1) has been reported for use as an anti-hypertensive and as an inhibitor of platelet aggregration. (U.S. Pat. No. 5,137,912, issued 1992).
Zanthoxylum (also referred to in the literature as Xanthoxylum), a member of the Yellow Wood family (Rutaceae), is a widely distributed genus of plants which has more than thirty species. Two species of Zanthoxylum are indigenous to the mainland of the United States: Z. americanum Mill. (Northern prickly Ash) and Z. clava-herculis L. (Southern prickly Ash), these two species are referred to herein collectively as Prickly Ash. Prickly Ash, commonly known as the toothache tree, is a shrub or small tree, 5-10 feet in height, which has had a long history as a botanical remedy. It is a traditional native North American remedy for toothaches. This plant has also been used as an internal treatment for ulcers, skin sores, diarrhea, indigestion and circulatory problems; and as an external remedy for chronic joint pain and rheumatism. The plant parts used are the bark and fruit. The stem bark of Zanthoxylum is a rich source of alkaloids and lignans. Chemical investigations on the bark of Prickly Ash have led to the isolation of a number of lignans and alkaloids, including both benzophenanthridine and aporphine alkaloids. Northern Prickly Ash is native to southern Canada and northern, central and western parts of the United States. The bark is harvested in spring and fall and the berries are collected in summer. Dry prickly ash bark powders are available in the botanical raw materials market. Southern Prickly Ash is native to central and southern United States.
There have been numerous reports of Prickly Ash and its active ingredients having diverse biological activity, including high protein kinase C inhibition activity (Chelerythrine), anti-hypertensive activity (Asarinin), antiplatelet activity (total alkaloids and coumarins), anti-malarial activity (crude extract), neuromuscular effects (crude extract), anti-sickling activity, (benzoic acid derivatives), cytotoxic activity (alkaloids), and elevated cytochrome P450 (essential oil).
Terry et al. have disclosed a method of treating vascular disorders by administration of Xanthoxylum (Zanthoxylum). (Terry et al. U.S. Pat. No. 5,562,906, issued Oct. 8, 1996). Terry et al. did not disclose any specific compounds from the Zanthoxylum that could be used for this purpose. Other reported uses of extracts from the Zanthoxylum genus include use in herbal compositions (Japanese Patent No. 07324039JP, 1995); use in herbal powders for the treatment of addictive diseases (U.S. Pat. No. 5,198,230, 1993); use as a remedy for anemia and arthritis (U.S. Pat. No. 4,767,626, 1988); use in a cream to enhance male sexual function (Japan Patent No. 06211678JP, 1994); and use as a hair tonic (Japan Patent No.05201833JP, 1993).
Current products containing Prickly Ash bark as an ingredient include Multi nutrition Fruit Drink (minor ingredient); Pro-Essence(detoxic) herbal formula--aqueous extract (major ingredient); Circulatory tonic--aqueous extract (major ingredient); and Self defense (bark powder).